The microRNAs (miRNAs) constitute a class of newly discovered small, non-coding genomic RNAs. The miRNAs are numerous, phylogenetically conserved and appear to play important roles in development. By virtue of being complementary, or partially so, to specific mRNAs, they appear to act via two different mechanisms as negative genetic switches. The miRNAs are related to the RNA interference (RNAi) intermediates known as siRNAs, another class of small, non-coding RNAs that can likewise function as negative genetic switches. Both synthetic and DNA vector-generated RNAs of these two classes are useful tools for genome exploration, and in the future may be used therapeutically to turn off harmful genes. However, the instability of small RNA in serum may impede the exploitation of mi- and siRNAs as vertebrate therapeutic agents. Our goal is to design and develop a new class of mi- and siRNA delivery vectors that can be used both as genome exploration tools and therapeutic mi- and siRNA delivery agents with ribonuclease resistance. These new delivery vectors combine the best qualities of the DNA plasmid vectors with the unique advantages and controllability of chemically synthesized mi- and siRNAs. In the proposed research, we aim to design, make and study in vitro and in cell culture the utility of this new class of vector as a genome exploration tool, and to evaluate its feasibility as a future gene therapy tool acting at the level of mRNA control.